Genetic Variant NM_004960.4:c.684_686delCGG (chr16-31185081-TGGC-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_004960.4(FUS):c.684_686delCGG(p.Gly229del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000296 in 1,606,830 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G228G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

FUS
NM_004960.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.05

Publications

2 publications found

Variant links:

Genes affected

FUS (HGNC:4010): (FUS RNA binding protein) This gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]

FUS Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
amyotrophic lateral sclerosis type 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
juvenile amyotrophic lateral sclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tremor, hereditary essential, 4
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

FUS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004960.4

BP6

Variant 16-31185081-TGGC-T is Benign according to our data. Variant chr16-31185081-TGGC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 540283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000791 (120/151636) while in subpopulation AFR AF = 0.00208 (86/41322). AF 95% confidence interval is 0.00173. There are 4 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004960.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FUS	NM_004960.4	MANE Select	c.684_686delCGG	p.Gly229del	disruptive_inframe_deletion	Exon 6 of 15	NP_004951.1
FUS	NM_001170634.1		c.681_683delCGG	p.Gly228del	disruptive_inframe_deletion	Exon 6 of 15	NP_001164105.1
FUS	NM_001170937.1		c.672_674delCGG	p.Gly225del	disruptive_inframe_deletion	Exon 6 of 15	NP_001164408.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FUS	ENST00000254108.12	TSL:1 MANE Select	c.684_686delCGG	p.Gly229del	disruptive_inframe_deletion	Exon 6 of 15	ENSP00000254108.8
FUS	ENST00000380244.8	TSL:1	c.681_683delCGG	p.Gly228del	disruptive_inframe_deletion	Exon 6 of 15	ENSP00000369594.3
FUS	ENST00000566605.5	TSL:1	n.684_686delCGG		non_coding_transcript_exon	Exon 6 of 14	ENSP00000455073.1

Frequencies

GnomAD3 genomes

AF:

0.000667

AC:

101

AN:

151518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000361

AC:

AN:

232882

AF XY:

0.000340

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000750

Gnomad FIN exome

AF:

0.0000977

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000245

AC:

356

AN:

1455194

Hom.:

AF XY:

0.000257

AC XY:

186

AN XY:

723568

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

33366

American (AMR)

AF:

0.000486

AC:

AN:

43214

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26032

East Asian (EAS)

AF:

0.000658

AC:

AN:

39528

South Asian (SAS)

AF:

0.000314

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.0000762

AC:

AN:

52470

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000189

AC:

210

AN:

1108804

Other (OTH)

AF:

0.000250

AC:

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000791

AC:

120

AN:

151636

Hom.:

Cov.:

AF XY:

0.000850

AC XY:

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.00208

AC:

AN:

41322

American (AMR)

AF:

0.00105

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000389

AC:

AN:

5148

South Asian (SAS)

AF:

0.000209

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67874

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

FUS-related disorder

Benign:1

Sep 25, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not specified

Benign:1

Jun 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FFUS c.684_686delCGG (p.Gly231del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0003 in 1606830 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in FUS causing Amyotrophic Lateral Sclerosis Type 6 phenotype. To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 540283). Based on the evidence outlined above, the variant was classified as likely benign.

Inborn genetic diseases

Benign:1

Nov 04, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over